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In this paper we describe the preclinical evaluation of ^sup 99m^Tchydrazinonicotinyl-Tyr^sup 3^-octreotide (HYNIC-TOC) using different coligands for radiolabeling and a comparison of their in vitro and in vivo properties with ^sup 111^In-diethylenetriaminepentaacetic acid (DTPA)-octreotide. Methods: HYNIC-TOC was radiolabeled at high specific activities using tricine, ethylenediaminediacetic acid (EDDA), and tricine-nicotinic acid as coligand systems. Receptor binding was tested using AR42J rat pancreatic tumor cell membranes. Internalization and protein binding studies were performed, and biodistribution and tumor uptake were determined in AR42J tumor-bearing nude mice. Results: All ^sup 99m^Tc-labeled HYNIC peptides showed retained somatostatin-receptor binding affinities (K^sub d^ < 2.65 nM). Protein binding and internalization rates were dependent on the coligand used. Specific tumor uptake between 5.8 and 9.6 percentage injected dose per gram (%ID/g) was found for the ^sup 99m^Tc-labeled peptides, compared with 4.3 %ID/g for ^sup 111^In-DTPA-octreotide. Tricine as coligand showed higher activity levels in muscle, blood, and liver, whereas tricinenicotinic acid produced significant levels of activity in the gastrointestinal tract. EDDA showed the most promising overall biodistribution profile, with tumor-to-liver and tumor-to-gastrointestinal tract ratios similar to those obtained with ^sup 111^In-DTPA-octreotide, lower ratios in blood and muscle, but considerably higher tumor-to-kidney ratios. Conclusion: TOC can be radiolabeled to high specific activities using HYNIC as a bifunctional chelator. The high specific tumor uptake, rapid blood clearance, and predominantly renal excretion make ^sup 99m^Tc-EDDA-HYNIC-TOC a promising candidate for an alternative to ^sup 111^In-DTPA-octreotide for tumor imaging.
Key Words: somatostatin; octreotide; hydrazinonicotinamide; ^sup 99m^TC
J Nucl Med 2000; 41.1114-1119
Over the last few years, ^sup 111^In-diethylenetriaminepenta tic acid (DTPA)-octreotide has found widespread clinical applicability, especially in oncology (1-3). However, limitations, especially concerning availability, imaging properties, and costs, remain and have stimulated research on radiolabeling with many alternative radionuclides, including ^sup 90^Y and ^sup 161^Tb (4) for therapeutic applications; ^sup 68^Ga (5,) ^sup 64^Cu (6), and ^sup 18^F (7 for positron imaging; and, in particular, ^sup 99m^TC. Thus, ^sup 99m^Tc labeling of somatostatin analogues has been extensively studied, including attempts at direct labeling after reduction of the disulfide bridge (8,9) and the use of bifunctional chelators such as propyleneaminoxime (10), triamidomonothiols (11), and tetramines (12,13). One analogue based on a carbocyclic peptide and a ^sup 99m^Tc-N^sub 3^Schelating moiety (P829) has been studied extensively in clinical trials (14)....